FM 140 vs FM100 Study in Patients With Multiple Myeloma

• Sponsor: M.D. Anderson Cancer Center (Other)
• Overall Status: Completed
• CT.gov ID: NCT00505895
• Collaborator: (none)
• Enrollment: 52
• Location: 1
• Arms: 2
• Duration (Months): 136
• Patients Per Site Per Month: 0.4

Study Details

Study Description

Brief Summary

The goal of this clinical research study is to learn if there is a difference in transplant outcomes between two different doses of melphalan given in combination with fludarabine followed by transfusion of a related or unrelated volunteer donor's peripheral blood or bone marrow progenitor cells (allogeneic stem cell transplant) in patients with multiple myeloma. This study will also look at whether treatment with a antibody called rituximab against a specific type of lymphocyte (B cell) will reduce the risks of developing graft versus host disease after transplant. The safety of these treatments will also be compared.

Condition or Disease	Intervention/Treatment	Phase
Multiple Myeloma	Drug: Melphalan; Drug: Fludarabine; Procedure: Stem Cell Infusion; Drug: Rituximab	Phase 2

Detailed Description

Fludarabine is a chemotherapy drug that is used in various diseases. Melphalan is a chemotherapy drug that has been widely used in the treatment of multiple myeloma for many years.

Before beginning therapy, patients will have a complete work-up. This includes a bone marrow aspiration and biopsy, bone survey, blood tests, and tests to check the heart and lung function. All patients will receive tacrolimus and methotrexate to prevent graft-versus-host disease.

Patients in this study will be randomly picked (as in the toss of a coin) to be in one of two treatment groups. There is an equal chance that a patient will be in either group.

Patients in the first group will receive fludarabine through the vein every day for four days. On the fourth day, patients will receive a dose of melphalan through the vein over 20 minutes. On the following day, patients will receive the donor cells as an infusion through their catheter.

Patients in the second group will receive fludarabine through the vein every day for four days. Patients in this group will receive a lower dose of melphalan through the vein over 20 minutes. After the last dose of fludarabine, patients will receive the donor cells as an infusion through their catheter the next day.

If you have an unrelated or a mismatched donor, you will receive the drug ATG (Thymoglobulin) by vein over 6 hours on Days -3, -2, and -1 (the 3 days before the transplant), to prevent graft versus host disease (GVHD) and to help engraftment.

Patients in both group will be receiving the monoclonal antibody called rituximab weekly starting on the fifth day before the stem cell transplant for a total of 4 doses.

Patients will remain in the hospital for about 4-6 weeks and in Houston Medical Center area at least 100 days after transplantation.

Patients whose disease gets worse will be taken off study. These patients will continue to be followed for survival.

This is an investigational study. All of the drugs used in this study are commercially available. The FDA has approved melphalan for the treatment of myeloma. Fludarabine is not approved for the treatment of myeloma but has been used for years as a way to prepare patients for transplant. About 30 to 60 patients will take part in this study. About 45 patients will be enrolled at M. D. Anderson.

Study Design

• Study Type: Interventional
• Actual Enrollment: 52 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Randomized Phase II Trial of Fludarabine/Melphalan 140 VS. Fludarabine/Melphalan 100 Followed By Allogeneic Peripheral Blood Stem Cell or Bone Marrow Transplantation for Patients With Multiple Myeloma
• Study Start Date: Jan 1, 2002
• Actual Primary Completion Date: May 1, 2013
• Actual Study Completion Date: May 1, 2013

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Fludarabine + Melphalan + Stem Cell Infusion Fludarabine 30 mg/m^2 intravenous (IV) daily over 30 minutes for 4 Days (Beginning Day -4). Melphalan 140 mg/m^2 IV over 20 minutes on Day -1. Stem Cell Infusion on Day 0. Rituximab 375 mg/m^2 IV infused starting on day -5.	Drug: Melphalan; Arm 1 = 140 mg/m^2 intravenous over 20 Minutes on Day -1; Arm 2 = 100 mg/m^2 intravenous over 20 Minutes on Day -1.; Other Names: Alkeran ; Drug: Fludarabine; 30 mg/m^2 intravenous daily over 30 Minutes for 4 Days (Beginning Day -4).; Other Names: Fludara Fludarabine Phosphate ; Procedure: Stem Cell Infusion; Stem Cell Infusion on Day 0.; Other Names: Allogeneic Peripheral Blood Stem Cell Transfusion APBSCT Bone Marrow Transplantation BMT ; Drug: Rituximab; 375 mg/m^2 intravenous on Day -5, +2 +9 and +16.; Other Names: Rituxan
Experimental: Fludarabine + Lower-Dose Melphalan + Stem Cell Infusion Fludarabine 30 mg/m^2 intravenous daily over 30 minutes for 4 Days (Beginning Day -4). Lower-Dose Melphalan 100 mg/m^2 intravenous over 20 minutes on Day -1. Stem Cell Infusion on Day 0. Rituximab 375 mg/m^2 intravenous infused starting on day -5.	Drug: Melphalan; Arm 1 = 140 mg/m^2 intravenous over 20 Minutes on Day -1; Arm 2 = 100 mg/m^2 intravenous over 20 Minutes on Day -1.; Other Names: Alkeran ; Drug: Fludarabine; 30 mg/m^2 intravenous daily over 30 Minutes for 4 Days (Beginning Day -4).; Other Names: Fludara Fludarabine Phosphate ; Procedure: Stem Cell Infusion; Stem Cell Infusion on Day 0.; Other Names: Allogeneic Peripheral Blood Stem Cell Transfusion APBSCT Bone Marrow Transplantation BMT ; Drug: Rituximab; 375 mg/m^2 intravenous on Day -5, +2 +9 and +16.; Other Names: Rituxan

Outcome Measures

Primary Outcome Measures

1. Number of Participants With Successful Engraftment at Day 100 [Day 100]

Secondary Outcome Measures

1. Acute Grade II-IV Graft Versus Host Disease (GVHD) [GVHD grading weekly during first 100 days; Annual examinations for nine year study period]

   Effects of Rituximab as measured by percentage of participants with Acute and Chronic Graft Versus Host Disease (GVHD) incidences after allogeneic transplantation. GVHD occurring anytime after day 90 post transplant was considered chronic GVHD; otherwise it was considered acute GVHD. Acute GVHD status defined as GVHD with maximum grade ≥2. Clinical grading of Acute GVHD (Thomas et al., New England Journal of Medicine (NEJM), 229:895, 1975): Grade 1 to 4.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 70 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Patients with Multiple Myeloma in any of the following disease categories: a) Primary Refractory considered poor candidate for autologous transplant, b) Remission Consolidation in patients with Chromosome 13 abnormalities or plasma cell leukemia, c) All relapsing patients.

2. Age up to 70 years.

3. Related or unrelated donor who is HLA-compatible in at least 9/10 alleles (A,B, C, DRB1 and DQ) by molecular techniques.

4. Zubrod Performance Score (PS)<2.

5. Life expectancy is not severely limited by concomitant illness. Left ventricular ejection fraction >40%. No uncontrolled arrhythmias or symptomatic cardiac disease. Forced expiratory volume in 1 second (FEV1), forced vital capacity (FVC) and diffusing capacity of the lungs for carbon monoxide (DLCO) >40%.

6. Patient and donor or guardian willing and able to sign informed consent.

Exclusion Criteria:

1. Patients with active central nervous system (CNS) disease are ineligible for this study as documented by clinical symptoms and/or testing.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	UT MD . Anderson Cancer Center	Houston	Texas	United States	77030

Sponsors and Collaborators

• M.D. Anderson Cancer Center

Investigators

• Principal Investigator: Muzaffar H. Qazilbash, MD, UT MD Anderson Cancer Center

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• The University of Texas M.D.Anderson Cancer Center

Publications

None provided.

• Responsible Party: M.D. Anderson Cancer Center
• ClinicalTrials.gov Identifier: NCT00505895
• Other Study ID Numbers: ID01-518
• First Posted: Jul 25, 2007
• Last Update Posted: Oct 17, 2014
• Last Verified: Oct 1, 2014

• Keywords provided by M.D. Anderson Cancer Center: Multiple Myeloma; Fludarabine; Fludara; Fludarabine Phosphate; Melphalan; Alkeran; Stem Cell Infusion; Stem Cell Transfusion; SCT; Allogeneic Peripheral Blood Stem Cell Transfusion; APBSCT; Bone Marrow Transplantation; BMT; Rituxan; Rituximab; FM140; FM100
• Additional relevant MeSH terms: Multiple Myeloma; Neoplasms, Plasma Cell; Vidarabine; Rituximab; Fludarabine; Fludarabine phosphate; Melphalan

Study Results

Participant Flow

Recruitment Details	Recruitment Period: January 18, 2002 to July 27, 2011. All recruitment done in a medical clinical setting.
Pre-assignment Detail	Of the 52 participants enrolled, two were not included due to one patient experiencing pulmonary complication and another not completing the study follow up requirement.

Arm/Group Title	Fludarabine + Melphalan + Stem Cell Infusion	Fludarabine + Lower-Dose Melphalan + Stem Cell Infusion
Arm/Group Description	Fludarabine 30 mg/m^2 intravenous (IV) daily over 30 minutes for 4 Days (Beginning Day -4). Melphalan 140 mg/m^2 IV over 20 minutes on Day -1. Stem Cell Infusion on Day 0. Rituximab 375 mg/m^2 IV infused starting on day -5.	Fludarabine 30 mg/m^2 IV daily over 30 minutes for 4 Days (Beginning Day -4). Lower-Dose Melphalan 100 mg/m^2 IV over 20 minutes on Day -1. Stem Cell Infusion on Day 0. Rituximab 375 mg/m^2 IV infused starting on day -5.
Period Title: Overall Study
STARTED	27	23
COMPLETED	27	23
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Fludarabine + Melphalan + Stem Cell Infusion	Fludarabine + Lower-Dose Melphalan + Stem Cell Infusion	Total
Arm/Group Description	Fludarabine 30 mg/m^2 intravenous (IV) daily over 30 minutes for 4 Days (Beginning Day -4). Melphalan 140 mg/m^2 IV over 20 minutes on Day -1. Stem Cell Infusion on Day 0. Rituximab 375 mg/m^2 IV infused starting on day -5.	Fludarabine 30 mg/m^2 intravenous daily over 30 minutes for 4 Days (Beginning Day -4). Lower-Dose Melphalan 100 mg/m^2 intravenous over 20 minutes on Day -1. Stem Cell Infusion on Day 0. Rituximab 375 mg/m^2 intravenous infused starting on day -5.	Total of all reporting groups
Overall Participants	27	23	50
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	52	53	53
Sex: Female, Male (Count of Participants)
Female	8 29.6%	12 52.2%	20 40%
Male	19 70.4%	11 47.8%	30 60%
Region of Enrollment (participants) [Number]
United States	27 100%	23 100%	50 100%

Outcome Measures

1. Primary Outcome

Title	Number of Participants With Successful Engraftment at Day 100
Time Frame	Day 100

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Fludarabine + Melphalan + Stem Cell Infusion	Fludarabine + Lower-Dose Melphalan + Stem Cell Infusion
Arm/Group Description	Fludarabine 30 mg/m^2 intravenous (IV) daily over 30 minutes for 4 Days (Beginning Day -4). Melphalan 140 mg/m^2 IV over 20 minutes on Day -1. Stem Cell Infusion on Day 0. Rituximab 375 mg/m^2 IV infused starting on day -5.	Fludarabine 30 mg/m^2 IV daily over 30 minutes for 4 Days (Beginning Day -4). Lower-Dose Melphalan 100 mg/m^2 IV over 20 minutes on Day -1. Stem Cell Infusion on Day 0. Rituximab 375 mg/m^2 IV infused starting on day -5.
Measure Participants	27	23
Number [participants]	27 100%	23 100%

2. Secondary Outcome

Title	Acute Grade II-IV Graft Versus Host Disease (GVHD)
Description	Effects of Rituximab as measured by percentage of participants with Acute and Chronic Graft Versus Host Disease (GVHD) incidences after allogeneic transplantation. GVHD occurring anytime after day 90 post transplant was considered chronic GVHD; otherwise it was considered acute GVHD. Acute GVHD status defined as GVHD with maximum grade ≥2. Clinical grading of Acute GVHD (Thomas et al., New England Journal of Medicine (NEJM), 229:895, 1975): Grade 1 to 4.
Time Frame	GVHD grading weekly during first 100 days; Annual examinations for nine year study period

Outcome Measure Data

Analysis Population Description

For the acute GVHD analysis, only 48 patients' data were available.

Arm/Group Title	Fludarabine + Melphalan + Stem Cell Infusion	Fludarabine + Lower-Dose Melphalan + Stem Cell Infusion
Arm/Group Description	Fludarabine 30 mg/m^2 intravenous (IV) daily over 30 minutes for 4 Days (Beginning Day -4). Melphalan 140 mg/m^2 IV over 20 minutes on Day -1. Stem Cell Infusion on Day 0. Rituximab 375 mg/m^2 IV infused starting on day -5.	Fludarabine 30 mg/m^2 IV daily over 30 minutes for 4 Days (Beginning Day -4). Lower-Dose Melphalan 100 mg/m^2 IV over 20 minutes on Day -1. Stem Cell Infusion on Day 0. Rituximab 375 mg/m^2 IV infused starting on day -5.
Measure Participants	27	23
Acute GVHD	22 81.5%	21 91.3%
Chronic GVHD	29 107.4%	48 208.7%

Adverse Events

Time Frame	The end of active treatment was the day of the drug administration of Rituximab on Day+16. Study participation was from baseline to 100 days after transplantation. Overall study period was March 2002 to May 2013.
Arm/Group Title	Fludarabine + Melphalan + Stem Cell Infusion		Fludarabine + Lower-Dose Melphalan + Stem Cell Infusion
Arm/Group Description	Fludarabine 30 mg/m^2 intravenous (IV) daily over 30 minutes for 4 Days (Beginning Day -4). Melphalan 140 mg/m^2 IV over 20 minutes on Day -1. Stem Cell Infusion on Day 0. Rituximab 375 mg/m^2 IV infused starting on day -5.		Fludarabine 30 mg/m^2 IV daily over 30 minutes for 4 Days (Beginning Day -4). Lower-Dose Melphalan 100 mg/m^2 IV over 20 minutes on Day -1. Stem Cell Infusion on Day 0. Rituximab 375 mg/m^2 IV infused starting on day -5.
All Cause Mortality
	Fludarabine + Melphalan + Stem Cell Infusion		Fludarabine + Lower-Dose Melphalan + Stem Cell Infusion
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Fludarabine + Melphalan + Stem Cell Infusion		Fludarabine + Lower-Dose Melphalan + Stem Cell Infusion
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	23/27 (85.2%)		16/23 (69.6%)
Blood and lymphatic system disorders
Secondary graft failure	0/27 (0%)	0	1/23 (4.3%)	1
Gastrointestinal disorders
Diarrhea	2/27 (7.4%)	2	0/23 (0%)	0
Dysphagia	1/27 (3.7%)	1	0/23 (0%)	0
General disorders
Death	23/27 (85.2%)	23	16/23 (69.6%)	16
Hepatobiliary disorders
Elevated ALT	1/27 (3.7%)	1	0/23 (0%)	0
Investigations
Infection	3/27 (11.1%)	5	6/23 (26.1%)	14
Metabolism and nutrition disorders
Nervous system disorders
Seizures	1/27 (3.7%)	1	0/23 (0%)	0
Altered mental status	0/27 (0%)	0	1/23 (4.3%)	1
Renal and urinary disorders
Elevated creatinine	0/27 (0%)	0	1/23 (4.3%)	1
Respiratory, thoracic and mediastinal disorders
Pneumonitis	2/27 (7.4%)	2	1/23 (4.3%)	1
Pulmonary hemorrhage	1/27 (3.7%)	1	0/23 (0%)	0
Skin and subcutaneous tissue disorders
Rash	0/27 (0%)	0	1/23 (4.3%)	1
Other (Not Including Serious) Adverse Events
	Fludarabine + Melphalan + Stem Cell Infusion		Fludarabine + Lower-Dose Melphalan + Stem Cell Infusion
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	8/27 (29.6%)		10/23 (43.5%)
Cardiac disorders
Hypertension	1/27 (3.7%)	1	1/23 (4.3%)	1
Dysarrhythmia	0/27 (0%)	0	1/23 (4.3%)	1
Eye disorders
Conjunctivitis	1/27 (3.7%)	1	2/23 (8.7%)	2
Gastrointestinal disorders
Diarrhea	5/27 (18.5%)	5	6/23 (26.1%)	6
Dysphagia	3/27 (11.1%)	3	5/23 (21.7%)	5
Nausea	7/27 (25.9%)	8	10/23 (43.5%)	11
General disorders
Volume overload	1/27 (3.7%)	1	3/23 (13%)	3
Lethargy	0/27 (0%)	0	1/23 (4.3%)	1
Hepatobiliary disorders
Elevated Alkaline Phosphatase	0/27 (0%)	0	2/23 (8.7%)	2
Elevated ALT	0/27 (0%)	0	2/23 (8.7%)	2
Infections and infestations
Fever	3/27 (11.1%)	3	3/23 (13%)	3
Infection	2/27 (7.4%)	2	2/23 (8.7%)	3
Nervous system disorders
Dizziness	1/27 (3.7%)	1	1/23 (4.3%)	1
Neuropathy	0/27 (0%)	0	1/23 (4.3%)	1
Renal and urinary disorders
Hematuria	1/27 (3.7%)	1	1/23 (4.3%)	1
Elevated Creatinine	1/27 (3.7%)	1	1/23 (4.3%)	1
Skin and subcutaneous tissue disorders
Rash	2/27 (7.4%)	3	3/23 (13%)	3

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.